This application proposes to isolate novel PrPc-specific single-chain variable fragment antibodies that will be utilized in a passive immuno-therapy on cell lines chronically infected with PrPsc and mobilized into herpes simplex virus amplicon and recombinant adeno-associated virus, serotype 2 platforms to be characterized for future utility in an in vivo therapy strategy. A combinatorial phage display library expressing linked human immunoglobin heavy and light chains variable regions has been used to enrich for scFv phage specific to recombinant mouse prion protein (recMoPrP). Identified sequences will be expressed, pudfied and assessed for functionality. Purified Prp-specific scFvs will be assessed for efficacy in positively effecting Prpsc-accumulation in established chronically infected cell-line models for murine prion disease by treatment with varying concentrations of purified PrP-specific scFvs. Treatment efficacy will be assessed via immuno blot analysis and sensitivity to proteinase K treatment. Isolated scFv sequences will be subcloned and packaged in-frame with a eukaryotic secretion signal and a c-myc epitope tag into HSV amplicon and rAAV2 vectors. An In vivo time course study in c57Bi/6 mice will assess expression levels, kinetics, and migration from intracerebral (IC) administration site via IHC.